Patients with HR+/HER2- Metastatic Breast Cancer Treated with CDK4/6 Inhibitors: A Real-World Study in Italy

Introduction: PIK3CA (encoding phosphatidylinositol 3-kinase alpha [PI3Kα]) is a driver oncogene mutated (mut) in ~40% of HR+, HER2- ABCs, leading to endocrine therapy (ET) resistance and poor prognosis. Alpelisib (ALP) is the first oral α-selective PI3K inhibitor and degrader approved in this patient (pt) population. Primary analyses of Cohorts A and B from BYLieve, an ongoing Phase II noncomparative study, demonstrated efficacy and a consistent safety profile of ALP + ET (fulvestrant [FUL] or letrozole [LET]) in pts with PIK3CA-mut, HR+, HER2- ABC in the post CDK4/6i setting. Post hoc analyses of ALP benefit in pts with centrally confirmed PIK3CA mut, based on median duration of prior CDK4/6i, supported the efficacy of ALP + ET in CDK4/6i-resistant, HR+, HER2- ABC. Here we assessed whether those who achieved a short duration of disease control (6-month [mo] cutoff), with prior CDK4/6i + ET received clinical benefit with ALP + ET. Methods: In Cohorts A and B, pts with PIK3CA-mut, HR+, HER2- ABC had received CDK4/6i + aromatase inhibitor (AI) or FUL, respectively, as immediate prior therapy (majority in first line). Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided based on duration of prior CDK4/6i therapy (≤6 mo or >6 mo), and the association of progression-free survival (PFS) with this covariate was analyzed using a stratified log-rank test and Cox Proportional Hazards model. A 6-mo cutoff was selected based on the ESO-ESMO ABC5 cutoff for primary ET resistance, as current guidelines do not specify cutoffs for CDK4/6i resistance. This analysis is based on the PFS endpoint and included pts for whom duration of prior CDK4/6i therapy was known. Results: Of the 121 pts in Cohort A with centrally confirmed PIK3CA-mut disease (modified full analysis set, mFAS), 120 had duration of prior CDK4/6i available; 26 had CDK4/6i for ≤6 mo and 94 for >6 mo, with similar demographics/disease characteristics between subgroups. The hazard ratio (HR) of median PFS (mPFS) between the ≤6-mo group and >6-mo group was 0.50 (95% confidence interval [CI], 0.27-0.94), indicating a lower risk of progression in the ≤6-mo group, with mPFS 10.0 mo (95% CI, 5.55-not estimable) and 6.0 mo (95% CI, 5.16-8.31), respectively. Grade ≥3 adverse events (AEs) were experienced by 67.5% (n=85) of all pts (safety set) in Cohort A and by 76.9% (n=20)/65.0% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Of the 115 pts in Cohort B with centrally confirmed PIK3CA-mut disease (mFAS), 113 had duration of prior CDK4/6i available; 31 had CDK4/6i for ≤6 mo and 82 for >6 mo, with similar demographics/disease characteristics between subgroups. The HR of mPFS between the ≤6-mo and >6-mo groups was 0.76 (95% CI, 0.47-1.23), with the wide CI indicating no difference in risk of progression between subgroups, and mPFS was 5.9 mo (95% CI, 3.55-10.97) and 5.6 mo (95% CI, 3.68-7.10), respectively. Grade ≥3 AEs were experienced by 69.9% (n=86) of all pts (safety set) in Cohort B and by 63.6% (n=21)/72.2% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Conclusions: This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with >6-mo duration of disease control, with a comparable safety profile. This confirms targeting PI3Kα with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy. Citation Format: Stephen Chia, Eva M Ciruelos, Hope S Rugo, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Nicholas Turner, Ennan Gu, Christina Arce, Murat Akdere, Dejan Juric. Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or >6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-08.

The phosphatidylinositol-3-kinase (PI3K) pathway is mutated and aberrantly activated in breast and other cancers and plays a key role in cancer cell proliferation and survival.1 2 The PI3K pathway is deregulated through a variety of mechanisms, including mutation or amplification of PI3K, loss or inactivation of the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ), as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.3 4 Activating mutations in PIK3CA , the gene encoding the alpha isoform (p110 α) catalytic subunit of PI3K, is present in up to 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers5 6 and represents a molecular target to personalise therapy of selected patients with breast cancer.2 Standard of care therapy for advanced HR-positive/HER2-negative breast cancers consists on endocrine therapy with or without the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.7 Therapy-resistance inevitably occurs in the majority of patients. The rationale of combining PI3K inhibitors and endocrine therapy is to synergistically inhibit both the PI3K and ER pathways.8 Initial trials of pan-PI3K inhibitors plus endocrine therapy for patients with advanced breast cancer showed modest benefit with high rates of toxicity limiting their clinical drug development.9–11 Selective isoform-specific PI3K inhibitors, such as an α-specific PI3K inhibitor, have subsequently revealed activity with less toxicity.12 13 The phase III SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) trial investigated the efficacy and safety of alpelisib, a α-specific class-I PI3Kinhibitor, plus fulvestrant versus placebo plus fulvestrant in patients with metastatic HR-positive/HER2-negative breast cancer who had received endocrine therapy beforehand.14 About 85.6% of patients …

Introduction: Endocrine therapy (ET) is a standard first-line (1L) therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) MBC, but treatment resistance eventually emerges. Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is implicated in ET resistance; thus, combined ET and CDK4/6 inhibition is a rational approach to prolong disease control and delay cytotoxic therapy. We summarize available Phase 3 data of CDK4/6 inhibitors (CDK4/6i) + ET for the 1L treatment of HR+, HER2- MBC, and highlight ongoing studies. Methods: PubMed was searched for: “advanced breast cancer” AND (“first” OR “initial” OR "previously untreated") AND (ribociclib OR palbociclib OR abemaciclib). Results were manually filtered for Phase 3 studies of 1L treatment. Abstracts at AACR, ASCO, ESMO, and SABCS from 2016-2017 were also considered; clinicaltrials.gov was searched for ongoing trials. Results: PubMed yielded 42 results, with 5 relevant after filtering; key congresses resulted in 34 abstracts. Four randomized Phase 3 trials investigating 1L CDK4/6i + ET reported primary data and subgroup analyses. PALOMA-2 (palbociclib [PAL] + letrozole [LET]), MONALEESA-2 (ribociclib [RIB] + LET), and MONARCH-3 (abemaciclib [ABE] + nonsteroidal [NS] aromatase inhibitor [AI]) included postmenopausal women with HR+, HER2- MBC. Across the studies, median progression-free survival (PFS) with ET alone was 14.5-16.0 months, and was significantly prolonged with addition of a CDK4/6i: PAL 24.8 months (HR 0.58), RIB 25.3 months (HR 0.57), and ABE not reached (HR 0.54), all p<0.001. To date, no study has reported an overall survival advantage. PFS data from relevant subgroup analyses and comparison of study populations will be presented. Most common adverse events (>50% in any study) were neutropenia (PAL all-grade 80%/Grade 3 or 4 66%; RIB 74%/59%; ABE 41%/21%), diarrhea (PAL 26%/1%; RIB 35%/1%; ABE 81%/10%), nausea (PAL 35%/<1%; RIB 52%/2%; ABE 39%/1%), and infections (PAL not reported/4%; RIB 50%/4%; ABE 39%/5%). The MONALEESA-7 trial of RIB + tamoxifen/NSAI + goserelin, the only study in premenopausal women with ovarian suppression, met its PFS primary endpoint. Ongoing studies of CDK4/6i + 1L ET include: PAL + LET in postmenopausal Asian women (PALOMA-4), PAL + tamoxifen (NCT02668666) and RIB + LET (CompLEEment-1) in men and pre/postmenopausal women, PAL + AI followed by PAL + fulvestrant (vs continued PAL + AI) after emergence of ESR1 mutations (confer resistance to AIs) and before disease progression (PADA-1), and assessment of mechanisms of resistance to RIB + LET (NCT03050398). Conclusion: Phase 3 trials support CDK4/6 inhibition + ET for the 1L treatment of women with HR+, HER2- MBC. Ongoing trials are evaluating the safety and efficacy of CDK4/6i with other ET, in more diverse populations, continuation of CDK4/6 inhibition after first progression, and mechanisms of resistance. Citation Format: Kent F. Hoskins, Paul Richards, Kari Wisinski. First-line CDK4/6 inhibitor treatment for HR+, HER2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1615.

e13030 Background: CDKi with endocrine therapy (ET) is approved treatment of metastatic HR+/HER2- breast cancer based on PFS benefit vs ET alone. Outcomes data following CDKi discontinuation (dc) is limited, with trials ongoing in this setting. The reported phenomenon of rapid progression within 4 months of CDKi dc raises concern over CDKi impact on HR+/HER2- MBC biology. This study aims to define outcomes after CDKi dc and identify predictors of progression. Methods: This is a retrospective review of women ≥18 years with HR+/HER2- MBC who received CDKi between 4/1/14 and 12/1/19. Patient and tumor characteristics, pre and post CDKi tx, and reason for CDKi dc were collected. Time to event outcomes from date of CDKi dc (primary = PFS, secondary = Overall Survival, OS) were analyzed with Kaplan Meier estimators and Cox regression. Results: Analysis included 140 patients (median age 65 years), with most MBC (84%) arising from earlier stage disease. 51% of MBCs had visceral disease, and 66% received tx prior to CDKi. The most common CDKi was palbociclib (93%); and most common ET were letrozole (52%) and fulvestrant (40%). Median CDKi tx duration was 9 months (3.5 – 17.4) with 80% dc due to progression. Post CDKi txs included chemotherapy (44%), ET (24%), targeted tx (21%), no further tx (7%) and CDKi tx (4%). Median follow up was 12 months. mPFS post CDKi dc were 6.5 months (95% CI: 5.0 – 7.9) and 11.3 months (95% CI: 4.6 – 23.7) in patients who dc CDKi due to progression or other reasons, respectively (HR 1.77, 95%CI: 1.10-2.85). Among 112 patients who progressed on CDKi, estimated 4-month incidence of post CDKi progression or death was 31% (Table ). mOS post CDKi dc was 15.4 months (95%CI: 13.3-19.0) and mOS post CDKi initiation was 26.5 months (95% CI: 23.3 – 34.3). Visceral disease (HR 1.45, 95%CI: 1.01-2.08) and progression as reason for CDKi dc (HR 1.77, 95%CI: 1.1-2.85) were predictors of PFS (p < 0.05). Receiving fulvestrant with CDKi (HR 1.42, 95%CI: 0.96-1.0), prior chemotherapy in the metastatic setting (HR = 1.39, 95% CI: 0.90 – 2.14), and shorter CDKi duration were associated with non-significant increased risk of PFS. Conclusions: Rapid progression or death at 4 months occurred in 31% of MBCs following CDKi dc due to progression. Ongoing studies to define clinical and molecular characteristics of rapidly progressing tumors are underway to develop targeted tx approaches and improve outcomes.[Table: see text]

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is the most common first-line (1L) treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC). Registrational studies for palbociclib (P), ribociclib (R), and abemaciclib (A) have shown consistent PFS benefit; nevertheless, overall survival (OS) results have been inconsistent. No head-to-head studies directly comparing CDK4/6i have been conducted, and although cross-trial comparisons can provide insights, they are limited by differences in trial design and patient population. We have used real-world evidence (RWE) data to directly compare real-world OS (rwOS) with different CDK4/6i when used as 1L treatment for patients with mBC treated in the USA. Methods: This retrospective open-cohort study used data from two US de-identified electronic health record-derived data sets: primary analyses were conducted using data from the Flatiron Health database, which were then verified using data derived from the Tempus database. Eligible patients had HR+/HER2− mBC and received 1L metastatic treatment with CDK4/6i + ET between January 1, 2016, and April 30, 2023 (Flatiron Health), or December 31, 2022 (Tempus). Patients were followed from the first date of 1L treatment until death or last known activity. Median rwOS for each CDK4/6i was estimated using the Kaplan–Meier methodology. Treatment effects were analyzed using adjusted Cox proportional hazards models, including covariate and propensity score adjustments. Subgroup analyses were also conducted on patients treated with CDK4/6i + aromatase inhibitors (AI) as well as in patients who had a treatment-free interval (TFI) >12 months between last adjuvant ET and metastatic diagnosis date and were then treated with CDK4/6i + AI. Results : 4,567 patients were selected from the Flatiron Health database (3,504, 575, and 488 treated with P, A, and R, respectively) and 612 from the Tempus database (494, 65, and 53, respectively). In the Flatiron Health database, median (95% CI) rwOS was 43.8 (41.7–46.6) months for P, 43.2 (34.5–48.8) months for A and 44.2 (37.3–51.1) months for R. Adjusted hazard ratios: 1.09 (95% CI: 0.89–1.33) for P versus A and 1.07 (95% CI: 0.90–1.28) for P versus R. Subgroup analyses also showed a similar risk of death between CDK4/6i for patients who received CDK4/6i + AI (2,334, 341, and 355 treated with P, A, and R, respectively. Adjusted hazard ratios 0.90 [95% CI: 0.66–1.23] for P versus A and 1.08 [95% CI: 0.88–1.33] for P versus R) and those with a TFI>12 months (2,226, 349 and 232 treated with P, A and R, respectively. Adjusted hazard ratios 0.91 [95% CI: 0.66–1.25] for P versus A and 1.11 [95% CI: 0.90–1.37] for P versus R). Findings were confirmed with Tempus data; adjusted hazard ratios indicated a similar risk of death between CDK4/6i: 0.92 (95% CI: 0.51–1.68) for P versus A and 1.14 (95% CI: 0.64– 2.05) for P versus R. Conclusions: Our findings, using mature follow-up data, showed similar rwOS outcomes when different CDK4/6i are combined with ET as 1L treatment for patients with HR+/HER2− mBC. Results were consistent across RWE databases. As 1L treatment evolves, these findings contribute to the ongoing development of combination strategies, such as novel oral selective estrogen receptor degraders, to improve clinical outcomes in patients with HR+/HER2− mBC and guide clinical decision-making. Citation Format: Adam Brufsky, Richard S. Finn, Otto Metzger, Rodrigo Goncalves, Cynthia Huang-Bartlett, Sameet Sreenivasan, Ula Nur, Jessica Davies, Alex Grigorenko. Real-world comparative efficacy of CDK4/6 inhibitors in first-line treatment of HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-30.

Background: Patients (pts) with endocrine therapy (ET)-resistant, hormone receptor+ (HR+), HER2– metastatic breast cancer (mBC) have a poor prognosis and may derive less benefit when treated with ET + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in the first-line (1L) setting. PIK3CA mutations occur in 35–40% of pts with HR+, HER2– mBC and are associated with poor prognosis. In the INAVO120 (NCT03006172) study, the addition of inavolisib, a PI3Kα inhibitor and mutant degrader, to fulvestrant plus palbociclib (a CDK4/6i) conferred a substantially longer progression-free survival (PFS) improvement in pts with PIK3CA-mutated (PIK3CAmut), HR+, HER2– mBC in the 1L, ET-resistant setting. This analysis aimed to evaluate baseline characteristics, PIK3CA mutation prevalence, and treatment outcomes in pts with HR+, HER2– mBC treated in the 1L, real-world (RW) setting, including those pts who met further INAVO120 criteria. Methods: This is a retrospective, observational study of de-identified, electronic health record-derived data from the United States Flatiron Health Network (thus is not human subjects research, which would have required institutional review board assessment/approval). Pts selected for inclusion in the study had recurrent HR+, HER2– mBC diagnosed between 2015 and 2023, and started 1L treatment within 90 days of mBC diagnosis. A cohort of pts with recurrent disease, prior ET, and any 1L treatment for mBC was defined (‘broad cohort’), as well as ‘INAVO120-like’ populations (subdivided based on receipt of fulvestrant + palbociclib, fulvestrant + CDK4/6i, or ET + CDK4/6i) that included further criteria such as ET resistance, Eastern Cooperative Oncology Group Performance Status 0–2, no bone-only disease, and no elevated HbA1c or glucose levels at baseline. Results: The broad cohort included 7096 pts, of whom, 922 met the further INAVO120 criteria (overall INAVO120-like population). All pts in the overall INAVO120-like population had received 1L CDK4/6i + ET; 514/922 pts received CDK4/6i + fulvestrant, of whom 339/514 received palbociclib as the CDK4/6i partner. 39–41% of the INAVO120-like populations (212/922, 120/514, and 82/339) tested positive for PIK3CA mutations. Fast progressors (relapse within ≤6 months [mo] of 1L treatment start) were more frequent in the INAVO120-like populations (35–38%) vs the broad cohort (25%). Race/ethnicity distribution, body mass index at mBC diagnosis, duration of adjuvant treatment and use of different CDK4/6is were similar between the ‘INAVO120-like’ populations and the broad cohort. Compared with the broad cohort, INAVO120-like pts were more likely to have visceral metastases (75–78% vs 48%), stage 3 disease at initial diagnosis (32–37% vs 29%) and a shorter time to mBC diagnosis (3.9–4.8 years vs 5.7 years). The INAVO120-like populations also had shorter RW median PFS (8.2–8.5 vs 13.0 mo), shorter RW median time to chemotherapy (16.2–21.7 vs 33.0 mo), and shorter RW median overall survival (27.0–29.7 vs 36.8 mo) compared with the broad cohort. PIK3CA mutation testing at any point was more frequent in pts in the INAVO120-like populations compared with the broad cohort (59–61% vs 45%); however, the proportion of pts tested for mutations prior to 1L treatment was numerically lower, but generally similar across cohorts: 9.5–11.8% (INAVO120-like) vs 12.4% (broad cohort). The PIK3CA mutation rates were similar across cohorts (39–41% vs 41%). Conclusions: These RW data from a large US, community-based oncology network suggest that pts meeting the INAVO120 criteria have poor outcomes with 1L ET+ CDK4/6i treatment, regardless of the type of ET and CDK4/6i partner. Pts with PIK3CAmut, HR+, HER2– mBC may derive more benefit from therapies targeting the PI3K pathway (since PIK3CA mutations are a predictive biomarker of response), as demonstrated in the INAVO120 study. Citation Format: Peter Lambert, Eirini Thanopoulou, Preet Dhillon. Real-world observational study of patients with endocrine-resistant, hormone receptor+, HER2- metastatic breast cancer in the first-line setting: Patient characteristics, PIK3CA mutation prevalence, treatments, and clinical outcomes [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-07-27.

Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-06.

Background: A cyclin dependent kinase 4/6 inhibitor (CDK4/6i) in combination with endocrine therapy has become standard of care for HR+/HER2- advanced/metastatic breast cancer (MBC). CDK4/6i dose adjustment is recommended based on individual safety and tolerability during the treatment of MBC. Clinical trial data demonstrated that Palbociclib (PAL) dose adjustment had no significant impact on progression-free survival (PFS). Small real-world studies have not demonstrated consistent outcomes associated with PAL dose adjustment, including real-world PFS (rwPFS) and overall survival (OS). Large real-world studies with longer follow-up are needed to understand patient characteristics and clinical outcomes associated with CDK4/6i dose adjustment. This study examined PAL dose adjustment and outcomes in HR+/HER2- MBC in routine clinical practice. Methods: Using Flatiron Health longitudinal database, we conducted a retrospective analysis of HR+/HER2- MBC patients who started PAL plus an aromatase inhibitor (AI) as first-line therapy between February 2015 and March 2020 (index period). Patients were assessed from start of PAL+AI to September 30, 2020 (data cutoff), death, or last medical activity, whichever came first. Dose adjustment was defined as a change of PAL daily dose compared to initial/previous prescription dose. Treatment duration was defined as months from start of PAL+AI to end of the treatment. OS was defined as months from start of PAL+AI to death. rwPFS was defined as months from start of PAL+AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Kaplan-Meier analysis was used to estimate treatment duration, rwPFS, and OS. Multivariable Cox proportional hazard regression models were performed to adjust for baseline characteristics: age, sex, race/ethnicity, healthcare practice type, initial diagnosis, Eastern Cooperative Oncology Group Performance Status, National Cancer Institute-Comorbidity Index, disease free interval from initial breast cancer to MBC diagnosis, bone only disease, lung/liver involvement, and number of metastatic sites. Results: A total of 1,324 patients received PAL+AI during the index period. Mean age was 67.1 years (SD=9.6), 99.2% were female, and 68.0% were white. Of these patients, 1,110 (83.8%) initiated PAL at 125 mg/day, 144 (10.9%) at 100 mg/day, 48 (3.6%) at 75 mg/day, and 22 (1.7%) did not have information about initial dose. Among 1,302 patients who had initial dose documented, 524 (40.3%) experienced dose adjustment. Comparted with patients without dose adjustment, those with dose adjustment were more likely to be white (71.8% vs 65.8%) and had a higher proportion of lung/liver involvement (35.5% vs 32.4%). Median follow-up was 28.5 and 22.6 months in patients with and without dose adjustment, respectively. Median treatment duration was longer in patients with dose adjustment than in those without dose adjustment (27.4, 95%CI = 24.5–30.6 vs 21.4, 95%CI = 19.7–26.5 months). Patients with and without dose adjustment showed similar median rwPFS (20.5, 95%CI=17.8–25.9 vs 19.6, 95%CI=16.9–21.7 months; unadjusted HR = 0.90, 95%CI = 0.77–1.04, p=0.162; adjusted HR = 0.89, 95%CI = 0.76–1.04, p=0.133). Median OS was significantly prolonged in patients with dose adjustment than in those without dose adjustment (57.8, 95%CI=49.0–NA vs 51.4, 95%CI=45.3-58.7 months; unadjusted HR = 0.72, 95%CI = 0.59–0.88, p=0.001; adjusted HR = 0.73, 95%CI = 0.59–0.89, p=0.002). Conclusions: Similar to other CDK4/6is, PAL dose adjustment is common in the treatment of HR+/HER2- MBC. PAL dose adjustment did not have significant effect on rwPFS but was associated with prolonged treatment duration and OS. Further research is needed to confirm these findings and understand the reasons for PAL dose adjustment in real-world settings. Citation Format: Rachel Layman, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Gabrielle B Rocque, Adam Brufsky. Real-world palbociclib dose adjustment and outcomes in HR+/HER2- metastatic breast cancer: Flatiron database analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-14.

Background: PAL is a first-in-class cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for the treatment of HR+/HER2− ABC. Two CDK4/6is are currently available in Japan; PAL and abemaciclib (ABE). CDK4/6i+endocrine therapy (ET) has shown significant clinical benefits compared to ET alone in clinical trials. CDK4/6i combination therapy is strongly recommended as a first-line (1L) treatment in global and Japanese treatment guidelines. However, no optimal subsequent treatment has been established after discontinuing treatment with CDK4/6i+ET. Substantial data are required to determine whether the available treatment options remain effective after CDK4/6i treatment. Here, we report the treatment pattern of subsequent therapy after PAL in a real-world setting in Japan to provide insights into the optimal subsequent therapy. Methods: This retrospective, observational study utilized a nationwide hospital-based medical claims database managed by Medical Data Vision (MDV). The MDV database, one of the largest medical databases in Japan, covers 26% of acute-care hospitals across Japan, including 226 cancer therapeutic facilities. We evaluated the data of patients who received PAL from September 2017 to June 2021 and subsequently received therapy. Any treatment for ABC initiated within 30 days was considered part of one regimen. The median time-to-treatment failure (TTF) of subsequent therapy was estimated using the Kaplan–Meier method. Results: From the database, we identified 1,170 patients with HR+/HER2− ABC who received PAL, among which 398 (34%) received combination therapy as 1L treatment. The median age at PAL initiation was 64 years (range 53–72), and 13.0% of the patients were pre-/peri-menopausal. Among the 398 patients, 224 (56.3%) received therapy after PAL+ET. Endocrine-based therapy was commonly used as the first subsequent therapy (n=136; 60.7%), including CDK4/6i+ET (n=70; 31.2%), ET alone (n=39; 17.4%), and everolimus+ET (n=27; 12.1%). Among the 81 (36.2%) patients who received chemotherapy as the first subsequent therapy, 27 (12.1%) received bevacizumab+chemotherapy. The median TTF (95% confidence interval [CI]) of the first subsequent therapy was 7.5 months (6.5–8.4), and that of each subsequent regimen is listed in Table 1. The median TTF (95% CI) for patients received CDK4/6i+ET as first subsequent therapy after PAL+ET was the longest among the regimens, 10.9 months (6.5–15.6). Among the 70 patients, 36 changed only CDK4/6i type, 17 changed only ET type, and 12 changed both CDK4/6i and ET types. The median TTF (95% CI) was 20.1 months (6.5– not reached [NR]), 8.7 months (2.9–11.2), and 7.7 months (2.6–NR), respectively. No obvious trend was observed between the TTF of PAL+ET as a 1L treatment and the TTF of subsequent ABE after the PAL+ET treatment. Conclusion: More than half the patients received endocrine-based therapy after PAL+ET as a 1L treatment, and the observed treatment duration was comparable to the results of clinical trials reported to date, even after PAL treatment. ET+targeted therapy and chemotherapy represent acceptable treatment options after PAL+ET. One-third of patients received CDK4/6i+ET after PAL+ET in Japanese clinical practice; however, further investigation is warranted to confirm that this treatment strategy is effective. Table 1. Median TTF of each subsequent therapy after PAL+ET Citation Format: Masataka Sawaki, Yasuaki Muramatsu, Kanae Togo, Hiroji Iwata. Real-world treatment duration of subsequent therapy after palbociclib (PAL) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-26.

Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-07.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the established first-line targeted therapy (TT) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2–) advanced breast cancer (ABC). TreatER+ight, the first prospective, real-world study evaluating the treatment patterns, safety and effectiveness of ET alone or ET + TT in Canadian patients with HR+, HER2– ABC (2016 to 2020) recorded ET as the standard of care (SOC) in the first interim analysis report. However, treatment with CDK4/6i combined with ET have rapidly evolved as the SOC in the metastatic setting. Methods: This prospective, multicenter, observational study (NCT02753686) enrolled patients with HR+, HER2‒ ABC with or without prior exposure to ET and up to one line of prior CT in the advanced setting. The patients were enrolled by the line of their therapy (first-line, second-line or third-line) and grouped into 2 cohorts (ET and ET + TT). Duration of therapy, and overall survival (OS) are estimated using Kaplan–Meier method. Here, we report the final outcome with CDK4/6i treatment evolution with sequencing strategy and duration in routine clinical practice. Results: At data cutoff (December 1, 2022), a total of 439 enrolled patients (ET, n=104; ET + TT, n=335) from 25 centers in Canada, constituted the full analysis set. The median age (range) was 71.5 (37.0–96.0) years in ET cohort and 65.0 (23.0-87.0) years in ET + TT cohort. About 84.6% and 66.4% were postmenopausal patients in the ET and ET + TT cohorts, respectively. Patients with ECOG PS scores 0 to 1 composed of 82.0% and 93.5% in the ET and ET + TT cohorts, respectively. In the overall population, ET alone and ET + CDK4/6i were the most common treatment received by patients in first-line (43.5% and 43.3%) and second-line (36.3% and 24.6%) treatment settings. In third-line treatment setting, CT was the most common treatment received by patients (38.4%). Conclusions: Data from final analysis of TreatER+ight have further confirmed the evolution to primary use of CDK4/6i-based combination therapy in the first-line setting for Canadian patients with HR+, HER2– ABC. Additional details on duration of therapy by CDK4/6i agents, overall survival data and age subgroup analysis will be presented at SABCS 2023 Table 1_Baseline characteristics, treatment patterns, and duration of treatment Citation Format: Catherine Doyle, Ana Elisa Lohmann, Nayyer Iqbal, Jan-Willem Henning, Swati Kulkarni, Nadia Califaretti, John Hilton, Cristiano Ferrario, Nathaniel Bouganim, Mihaela Mates, Stephanie Guillemette, Ricardo Leite, Stephen Chia. Impact of the introduction of CDK4/6 inhibitors on treatment duration in patients with HR+, HER2– advanced breast cancer: Final analysis of TreatER+ight, a Canadian prospective, real-world, observational study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-01.

Background Breast cancer survivors are at risk for mortality from cardiovascular diseases (CVD). CVD and their treatments can impact breast cancer treatment selection and clinical outcomes. A cyclin dependent kinase 4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is more effective than ET alone for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2) metastatic breast cancer (MBC). CDK4/6i plus ET is now the standard of care in the first-line setting for HR+/HER2 MBC. However, data on the effectiveness of CDK4/6i in MBC patients with CVD are limited. We compared overall survival (OS) and real-world progression-free survival (rwPFS) of palbociclib plus AI (PAL+AI) vs AI alone in HR+/HER2 MBC patients with CVD in routine US clinical practices. Methods The Flatiron Health longitudinal database contains electronic health records from >280 cancer clinics, representing >3 million actively treated cancer patients in the US. Using the Flatiron database, we conducted a retrospective analysis of 469 patients with HR+/HER2 MBC and CVD who started PAL+AI or AI as first-line therapy between February 2015 and March 2020. CVD prior to the initiation of PAL+AI or AI were identified based on their definitions within the National Cancer Institute-Comorbidity Index (NCI-CI), including myocardial infarction, congestive heart failure, peripheral vascular diseases, and cerebrovascular diseases. Patients were assessed from start of PAL+AI or AI to September 30, 2020 (data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PAL+AI or AI to death. rwPFS was defined as months from start of PAL+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Stabilized inverse probability treatment weighting (sIPTW) as primary analysis was used to balance baseline demographics and clinical characteristics. Cox proportional-hazards models were used to estimate the relative effectiveness of PAL+AI vs AI alone. Results Of the 469 eligible patients, 160 (34.1%) were treated with PAL+AI and 309 (65.9%) were treated with AI alone. Compared with AI-alone patients, those treated with PAL+AI were younger and were more likely to have de novo MBC, ≥2 metastatic sites, and lung/liver involvement. After sIPTW, patient characteristics were generally balanced. After sIPTW, median OS (95% confidence interval [CI]) was 40.7 months (30.956.0) in PAL+AI patients and 26.5 months (23.337.3) in AI patients (hazard ratio [HR]=0.732, 95% CI=0.5370.997, p=0.0476). Median rwPFS (95% CI) was 20.0 months (11.7–27.5) in PAL+AI patients and 12.5 months (9.718.3) in AI patients (HR=0.679, 95% CI=0.5120.900, p=0.0070). Consistent results were observed with multivariate Cox proportional-hazards models as sensitivity analysis. See Table for baseline patient characteristics and outcome results. Conclusions First-line PAL in combination with AI is associated with prolonged OS and rwPFS in patients with HR+/HER2 MBC and CVD in a real-world setting compared with AI alone. Further studies with larger cohorts and comprehensive assessments of comorbidities are needed to provide additional evidence of outcomes and safety of CDK4/6i plus AI for MBC patients with various comorbid conditions in routine clinical practice. Citation Format: Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Doris Makari, Rachel Layman, Hope Rugo. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-05.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-07.

Background Approximately 15% of patients (pts) with hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)- breast cancer will develop brain metastases (BM) (Kuksis et al, NeuroOnc 2021). Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) with an endocrine therapy partner are recommended 1st line treatments in HR+HER2- metastatic breast cancer (MBC). Preclinical models show that CDK4/6i can cross the blood brain barrier (BBB). In vitro assays have shown that abemaciclib crosses the BBB more effectively than palbociclib or ribociclib (George et al, Front Oncol 2021). The efficacy of CDK4/6i in patients with breast cancer BM is not well described. Methods We examined prior treatment data for 368 pts with HR+HER2- BM who received a CDK4/6i between 2015 to 2021. The primary endpoint was overall survival (OS) from the time of starting CDK4/6i after BM development. CNS progression free survival (PFS) was assessed in pts who received CDK4/6i after BM development. We examined the relationship between OS, type and timing of CDK4/6i in multivariate analyses. Statistical analyses were conducted using R 4.1.2 software. Results Of the total cohort of 368 pts, 23% (n=86) had de novo MBC and 77% (n=282) had relapsed MBC. At initial presentation of MBC 79% (n=290) of pts had no BM, 19% (n=71) had BM and extracranial disease and 2% (n=7) had BM only. 56% (n=205) received a CDK4/6i before BM development, 37% (n=136) received a CDK4/6i after BM development and 7% (n=27) received a CDK 4/6i both before and after BM development. The most common CDK4/6i used first was palbociclib (85%, n=312) followed by abemaciclib (13%, n=47) and ribociclib (2%, n=9). At the time of data cutoff 277 pts were dead, 55 were alive and 36 were lost to follow up. The median follow-up of surviving pts from BM development was 32 months. 163 pts received a CDK4/6i post BM: palbociclib (66%, n=108), abemaciclib (31%, n=51) and ribociclib (3%, n=4). Of these 163 pts 83% (n=136) received a CDK4/6i as their 1st or 2nd systemic treatment post BM. In the cohort of 163 pts who received a CDK4/6i post BM, 9% did not receive local BM therapy, 40% had whole brain radiotherapy (WBRT), 34% had stereotactic surgery (SRS) alone and 17% had surgery +/- SRS. The median CNS PFS for pts who received a CDK4/6i after BM was 21 months with palbociclib and 14 months with abemaciclib (p value 0.11). Too few pts received ribociclib for analysis. CNS PFS was 21 months for pts receiving a CDK4/6i only after BM development and 10 months for those who received CDK4/6i both before and after BM diagnosis (p = 0.01). Pts who died prior to CNS progression were censored. Median OS from the time of starting CDK4/6i after BM development for pts receiving a CDK4/6i only after BM development was 25 months versus 12 months for those who received it both before and after BM development (p = 0.03). There was no statistically significant difference in OS when adjusting for the type of local BM treatment received, time from initial MBC diagnosis to BM, or the Breast Graded Prognostic Assessment (GPA) score (Sperduto et al, IJROBP 2020). Conclusions This observation suggests that there is a greater OS benefit from the time of starting CDK4/6i after BM development in pts who receive CDK4/6i solely after BM development compared to pts who received a CDK4/6i both before and after BM development. This is not unexpected given the known OS benefit associated with early use of these agents. Our unique observation of longer CNS PFS for patients who did not receive CDK4/6i prior to BM but who received it afterward suggests that CDK4/6i exposure prior to BM development may lead to development of resistance mechanisms that reduces CNS efficacy upon rechallenging with CDK4/6i after BM development. There was no statistically significant difference in post-BM CNS PFS by type of CDK4/6i received. This motivates investigation of biomarkers for patient selection and our ongoing work in collecting a matched comparison cohort of HR+HER2- pts with BM who never received CDK4/6i. Citation Format: Sonya Chew Minmin, Yuan Chen, Daniel Kelly, Mark E. Robson, Andrew D Seidman. Characterization of breast cancer brain metastases overall and progression-free survival and timing of cyclin-dependent kinase 4/6 inhibitor use: Retrospective single institution experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-09.

TPS1109 Background: Endocrine therapy (ET) + CDK4/6i is standard of care for HR+, HER2− ABC; however, CDK4/6i resistance, in which the phosphatidylinositol-3-kinase (PI3K) pathway has a key role, remains challenging. Progression-free survival (PFS) for ≥ 2nd-line ET monotherapy post CDK4/6i is poor; prognosis may be worse in patients with a PI3KCA mutation. ALP (PI3K-α selective inhibitor and degrader) + FUL is approved by the European Medicines Agency (EMA) for HR+, HER2–, PIK3CA-mutated ABC after ET monotherapy. Outside the EMA, ALP + FUL approval includes post-CDK4/6i use. ALP + FUL has shown clinical activity and consistent safety in a small subpopulation in SOLAR-1 with prior CDK4/6i treatment (n = 9) and in BYLieve Cohort A (CDK4/6i + AI as immediate prior treatment; n = 121). The EPIK-B5 study aims to confirm the efficacy and safety of ALP + FUL in a larger population with HR+, HER2–, PIK3CA-mutated ABC with prior CDK4/6i + AI treatment. Methods: EPIK-B5 is a Phase III, randomized (1:1), double-blind, placebo-controlled study assessing the efficacy and safety of ALP (300 mg/d orally starting Cycle 1 Day 1 [C1D1]) + FUL (500 mg intramuscularly on C1D1 and C1D15, and D1 of subsequent cycles) in patients (N ≈ 234) with HR+, HER2–, PIK3CA-mutated ABC progressing on/after CDK4/6i + AI. Patients randomized to placebo + FUL can cross over to ALP + FUL after progression. Randomization is stratified by presence of lung and/or liver metastasis and prior CDK4/6i setting. Adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mutated ABC and ≥ 1 measurable lesion are eligible. The primary endpoint is PFS per blinded independent review committee assessment. Secondary endpoints include overall survival, overall response and clinical benefit rates, duration of and time to response, PFS by PIK3CA-mutation status in circulating tumor DNA, PFS on next-line treatment, time to definitive deterioration of ECOG status, quality of life (QoL), and safety and tolerability. Exploratory endpoints include biomarker analyses, additional QoL endpoints, and time to subsequent chemotherapy. Recruitment is ongoing, with enrollment planned over 2 years in 18 countries; completion of primary data collection is anticipated in 2026. Clinical trial information: NCT05038735; EUDRACT2021-001966-39.